title: Bcl-2 prolongs cell survival after Bax-induced release of cytochrome c.
abstract: Following exposure of cells to stimuli that trigger programmed cell death (apoptosis), cytochrome c is rapidly released from mitochondria into the cytoplasm where it activates proteolytic molecules known as caspases that specifically cleave the amino-acid sequence DEVD and are crucial for the execution of apoptosis. The protein Bcl-2 interferes with this activation of caspases by preventing the release of cytochrome c. Here we study these molecular interactions during apoptosis induced by the protein Bax, a pro-apoptotic homologue of Bcl-2. We show that in cells transiently transfected with bax, Bax localizes to mitochondria and induces the release of cytochrome c, activation of caspase-3, membrane blebbing, nuclear fragmentation, and cell death. Caspase inhibitors do not affect Bax-induced cytochrome c release but block caspase-3 activation and nuclear fragmentation. Unexpectedly, Bcl-2 also fails to prevent Bax-induced cytochrome c release, although it co-localizes with Bax to mitochondria. Cells overexpressing both Bcl-2 and Bax show no signs of caspase activation and survive with significant amounts of cytochrome c in the cytoplasm. These findings indicate that Bcl-2 can interfere with Bax killing downstream of and independently of cytochrome c release.
authors.affiliation: Institute of Biochemistry, University of Fribourg, Switzerland.
authors.forename: T
authors.initials: T
authors.lastname: Rossé
authors.forename: R
authors.initials: R
authors.lastname: Olivier
authors.forename: L
authors.initials: L
authors.lastname: Monney
authors.forename: M
authors.initials: M
authors.lastname: Rager
authors.forename: S
authors.initials: S
authors.lastname: Conus
authors.forename: I
authors.initials: I
authors.lastname: Fellay
authors.forename: B
authors.initials: B
authors.lastname: Jansen
authors.forename: C
authors.initials: C
authors.lastname: Borner
mesh_terms: D000818:Animals; D017209:Apoptosis; D053148:Caspase 3; D020169:Caspases; D002470:Cell Survival; D002478:Cells, Cultured; D003546:Cysteine Endopeptidases / Q000378:metabolism; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D003574:Cytochrome c Group / Q000378:metabolism*; D053938:DNA Fragmentation; D004789:Enzyme Activation; D006801:Humans; D008928:Mitochondria / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism*; D051381:Rats; D014162:Transfection; D014407:Tumor Cells, Cultured; D051028:bcl-2-Associated X Protein
chemical_list: C494826:BAX protein, human; C494828:Bax protein, rat; D015853:Cysteine Proteinase Inhibitors; D003574:Cytochrome c Group; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D051028:bcl-2-Associated X Protein; C505407:CASP3 protein, human; C505410:Casp3 protein, rat; D053148:Caspase 3; D020169:Caspases; D003546:Cysteine Endopeptidases